chr17-81510406-T-C

Variant names:

• chr17-81510406-T-C
• rs11549167
• ENST00000574671.6:n.1812A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001614.5(ACTG1):​c.*284A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 534,420 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (225 hom., cov: 32)
  • Exomes 𝑓: 0.018 (136 hom.)
• Consequence: ACTG1 NM_001614.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0950
• Publications: 6 publications found

Genes affected

ACTG1 (HGNC:144): (actin gamma 1) Actins are highly conserved proteins that are involved in various types of cell motility and in maintenance of the cytoskeleton. Three main groups of actin isoforms have been identified in vertebrate animals: alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton and as mediators of internal cell motility. Actin gamma 1, encoded by this gene, is a cytoplasmic actin found in all cell types. Mutations in this gene are associated with DFNA20/26, a subtype of autosomal dominant non-syndromic sensorineural progressive hearing loss and also with Baraitser-Winter syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

ACTG1 Gene-Disease associations (from GenCC):

• Baraitser-winter syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 20

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Baraitser-Winter cerebrofrontofacial syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-81510406-T-C is Benign according to our data. Variant chr17-81510406-T-C is described in ClinVar as [Benign]. Clinvar id is 1272736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.*284A>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.*284A>G		3_prime_UTR_variant	Exon 6 of 6		NP_001186883.1
ACTG1	NR_037688.3	n.1411+73A>G		intron_variant	Intron 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.*284A>G		3_prime_UTR_variant	Exon 6 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6131 AN: 152182 Hom.: 227 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0411

GnomAD4 exome AF: 0.0180 AC: 6861 AN: 382120 Hom.: 136 Cov.: 4 AF XY: 0.0174 AC XY: 3609 AN XY: 207994

African (AFR) AF: 0.0943 AC: 1064 AN: 11286

American (AMR) AF: 0.0203 AC: 539 AN: 26546

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 574 AN: 12384

East Asian (EAS) AF: 0.0221 AC: 401 AN: 18142

South Asian (SAS) AF: 0.0161 AC: 858 AN: 53454

European-Finnish (FIN) AF: 0.00516 AC: 93 AN: 18024

Middle Eastern (MID) AF: 0.0202 AC: 33 AN: 1630

European-Non Finnish (NFE) AF: 0.0127 AC: 2790 AN: 220482

Other (OTH) AF: 0.0252 AC: 509 AN: 20172

GnomAD4 genome AF: 0.0403 AC: 6140 AN: 152300 Hom.: 225 Cov.: 32 AF XY: 0.0399 AC XY: 2968 AN XY: 74464

African (AFR) AF: 0.101 AC: 4177 AN: 41544

American (AMR) AF: 0.0301 AC: 461 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3472

East Asian (EAS) AF: 0.0330 AC: 171 AN: 5188

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4832

European-Finnish (FIN) AF: 0.00555 AC: 59 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0135 AC: 918 AN: 68018

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

Alfa AF: 0.0289 Hom.: 14

Bravo AF: 0.0439

Asia WGS AF: 0.0400 AC: 137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.70
PhyloP100		0.095
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11549167; hg19: chr17-79477432;